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The world-spread epidemic of HIV (Human Immunodeficiency Virus, HIV) infection and a huge number of deaths and financial loss it causes every year remains it to be a major public health issue. The distribution of infections around the world is largely differentiated, with more than 80% of 36.7 million people currently living with HIV and more than two-thirds of 1.8 million newly infected people coming from Sub-Saharan Africa in 20161. Notably, more than half of the currently-infected are female, and women aging 15 to 24 years old in this area had an up to eight folds higher rates of HIV-1 incidence of infection and an up to 3.3 folds higher prevalence of HIV compared with their male counterparts.1 This indicates that women, especially young women, are much more vulnerable and susceptible to the HIV-1 acquisition; effective prevention strategies targeted on them are desperately needed.
Limitations of present prevention strategies call for more effective ways to curb the transmission speed in generalized epidemic religion. Condom use depends largely on if women have the negotiation power with their male partners about using it. The percentage of using condoms to prevent HIV infection is found to be much lower in regular partnerships than that in commercial sex workers2. One common situation in regular partnerships in South Africa is that in order to sustain emotional and material support from male partners, a young girl will not obey their partners’ willingness and choose not to use a condom or other prevention measure even if knowing the existence of risk3. Therefore, high coverage of free condom distribution does not guarantee a high frequency of use in a defined situation due to a combination of social and personal reasons. Voluntary testing, which proved to be effective in informing people of their infection status, also gained less-than-expected support by local people because of discrimination and fear towards the disease2. Another example is male circumcision. In many countries in Africa, poor sanitation condition and scarce medical resources make it inaccessible to normal people male circumcision so the achievement of proposed HIV prevention effect is unavailable. Barriers to realistic situation propel medical and public health workers to think about more direct and effective options.
Both oral pre-exposure prophylaxis and vaginal microbicides have become new candidates in clinical trials in the late decades. Oral prophylaxis has been found to be able to reduce the hazard of HIV-1 infection by 50% or more among several groups, including a man having sex with a man, drug users and heterosexual men and women in different areas in the world4. However, subsequent trials of some pre-exposure prophylaxis, including oral pills and vaginal gel, showed no evidence of preventing HIV-1 type acquisition in intervention groups compared with placebo groups1, 4. These trials required the subjects to take the pills on a daily basis or apply the gel each time before the coitus during the whole follow-up period, usually lasting for over 2 years. Under such onerous rules, it is understandable that the percentage of participants who can insist on the principles would decrease over time. Low adherence of participants was the main reason why some trials were interrupted, and also the primary barrier in accurately assessing the efficacy of the intervention4; the willingness of applying vaginal gel or taking oral pre-exposure prophylaxis drugs was inconsistent before and after initiation of the study. These indicate that even though gel or oral pre-exposure drugs have the potential to protect women from acquiring the HIV-1 infection, their daily use and coitus-dependent requirements largely restrict their impact among African sex-active and reproductive women. Consequently, a more convenient and acceptable product of pre-exposure prophylaxis is still scarce and needed.
Based on the enlightenment of previous trials, vaginal ring was selected as an optimal carrier for HIV-1 prevention drugs as it can be used in an easy and non-coitus dependent way. Once the ring is placed on the vagina, it does not need to be adaptor administered within a month, and it does not disturb coitus and cause no uncomfortable feelings to the users. These characters endow the ring the potential to perform a higher adherence in subjects. It became a promising candidate in clinical trials rapidly.
Outcomes of phase I and phase II clinical trials have shown that intravaginal rings can deliver dapivirine to the vaginal area for one month at concentrations over EC50(the concentration of a drug that gives a half-maximal response) for the HIV-1 type. There are no adverse events confirmed or possible to be related to the ring, which indicates it was safe and well tolerated in healthy HIV-negative women5. Basic pharmacokinetics of dapivirine, which is a non-nucleoside HIV-1 reverse-transcriptase inhibitor, was also clarified. This helps us judge if one person has used the ring as instructions by plasma concentration of dapivirine and residual amount in the returned ring. In addition, in vivo experiment, dapivirine was proved to be effective in protecting issues from acquiring HIV-1 infection6. These earlier trials support further development and research on dapivirine vaginal rings for pre-exposure prophylaxis in healthy women. Therefore, whether the ring can still work in phase 3, randomized, double-blind trials are of great importance to its final application in its targeted population. All of the results listed above made good preparations for the study and after receiving the financial support from the foundation, the trial was initiated.
When it comes to the detail of the study, investigators enrolled over 2600 women aging 18 to 45 in 4 high incidences of HIV infection African countries. Subjects were divided into intervention and placebo group by block randomization and followed-up for over 30 months. The vaginal ring containing dapivirine was placed and was expected to remain for a whole month. A new ring would be distributed after the monthly visit and the used ring would be collected to be tested on the residual amount of dapivirine to assess if the ring was used continuously in the past month. Another method to evaluate the adherence is to test if the plasma level of dapivirine of subjects reached some threshold value. The primary ending point is the infection of the HIV-1 virus.
Based on the person-years of each participant before ending or withdrawn points, Cox regression was used to analysis if there was any difference between groups in the probability of acquiring an infection during the nearly 3-year follow-up period. The hazard ratio between the groups was estimated and further analysis in the subgroups of age was conducted. There were two analysis patterns: one included all the data from the 15 sites and another abandoned data gathered in two of the 15 sites due to low adherence rate. According to the data from all sites, women in the intervention group had 27% (95%CI: 1%-46%, P=0.046) lower incidence rate of HIV-1 acquisition than that in the placebo group; this figure becomes 37%( 95%CI: 12%-56%, P=0.007) in analysis excluding 2 low-adherent sites. Among different age groups, women aging 21 years old or over were observed having much better prevention effectiveness than younger females with a hazard ratio of 0.44(95%CI: 0.29-0.69, P<0.001) compared with 1.27(95%CI: 0.69-2.33, P=0.45) in the younger group.
Generally, the study results reveal that the dapivirine vaginal ring was safe and acceptable by most participants; it was effective in protecting seronegative, sexually active women from being infected by HIV-1 in high prevalence areas. The effectiveness of prevention effect increased with the adherence and retention rate increasing. Besides, lacking protection in young women below 21 may be the result of both biological and behavioral characteristic, which needs to be further clarified.
The study has its strengths and limitations. Randomization created a balanced distribution of characters that may be related to trial in both groups, making the results in two groups comparable; double-blind design reduced bias from both subjects and investigators due to knowing experiment status, as participants usually behave differently from what they are if knowing their true status, and investigator would tend to conduct the trial in a way that deduces positive results. Besides, Participants are the most vulnerable population for potential HIV-1 infection and they are from nearly the most prevalent area, which constitutes the very same background as the future application setting of the vaginal ring. Consequently, the results here are very informative in helping us to accurately assess the very true potential performance of the intervention. Furthermore, the whole process of the study was conducted in an organized and restricted way so the data quality can be regarded as high and reliable. Researchers used two methods to confirm adherence of subjects, the residual amount in the returned ring and the plasma concentration of papaverine. They also compared the separate result of the two methods with the combinative result of them about adherence to examine the consistency, making sure the legitimacy of the chosen ways. In addition, 4 weeks after the last visit, subjects were required to finish a final questionnaire to test if they are HIV-1 positive, considering the delay of the seroconversion. This step avoided the underestimation of a number of infection. These design and details make the study a rational and reasonable one.
On the other hand, some limitations in designing and conducting were observed in this study. The authors mentioned that the primary objective of the study is to investigate the efficacy and safety of the ring, however, the subjects were also receiving routine HIV-1 prevention package during the follow-up time. This may mask the effect of the intervention if the degree of using the normal protection services was different between the two groups, which means the observed protective effect may be due to less frequent use of normal services in the placebo group or more use of them in the dapivirine group. The minimum plasma concentration of papaverine is 95pg per milliliter for acknowledging the continuous use of the ring during the month, however, this level can be reached even though the users use the ring for only 8 hours. The possibility of removing the ring during the month or during coitus period still exists. As a result, the adherence of the subjects may be overestimated. Besides, there was a discrepancy in some samples in results of the two methods, with low plasma dapivirine levels and low residual amount at the same time or high plasma levels and high residual amount of dapivirine simultaneously. This indicates that either the subjects pretend to be adherent or the methods used to evaluate adherence are not sensitive and reliable enough. Besides, according to the description, women were instructed how to insert and extract the ring, so the position and angle of the ring in the vagina may very possibly vary due to lack standardization. Some participants may place the ring wrongly, or violently insert or removing as to damage the tract, which would undermine the effectiveness of the ring and can increase the risk of being infected. This can distort the overall assessment of the intervention if the percentage of participants who do not know how to correctly apply the ring is different between the two groups. Finally, the statistical results of the study were not adequately convincing. The P value in survival analysis in 15 sites is 0.045, just below the threshold of a statistically significant value. The lower limit of 95% confidence interval is 1%, which means the true population hazard decline in intervention group can be very low. Even though the figure from only 13 sites was more satisfied, randomized trial tends to value more on “intention-to-treat” analysis result. Considering the trial has emerged sufficient numbers of new infection to satisfy the statistics power requirements7, the little tricky P value undermines the degree of the efficacy of the intervention.
The biggest innovation of the trial comes from the type of the intervention, a continuously drug-releasing non-coitus dependent vaginal ring. Considering the strength and limitations of the study, we can summarize that the study involves a few selection and information bias and confounding; the positive result is unlikely to be given by chance. With restricting implementation of the protocol, reliable data, careful analysis, and cautious interpretation, the final conclusion of the study was justified.
Based on the outcome of the study, there are several questions worthy of being further explored. The primary one is to investigate if the dapivirine ring can protect young women when the adherence becomes satisfied. Then we will know if lacking protection effect in young women is due to low adherence or the intervention lacking influence in this age group, which can guide us to find the right direction in trying to apply the vaginal ring better in them. The vaginal ring containing antivirus drugs is not only more user-friendly, lasting and non-coitus dependent, but also has a lower requirement in its transportation and storage than other pre-exposure prophylaxis microbicides like oral tenofovir and tenofovir gel7, which are great disadvantages when considering its application. Together with the positive result of the study, another further step can be comparing the cost-effectiveness of currently available pre-exposure prophylaxis microbicides to assess its practical use potential. This measure becomes critical in achieving the defined value of the ring as many low-income countries cannot afford to provide enough coverage for the targeted population of antivirus intervention. Targeted population of the vaginal ring is sexually active females aging 18 to 45 years old in Africa. However, the need to prevent HIV-1 infection is only one of the health needs of these people. Avoiding unplanned pregnancy, preventing and treating other sexually transmitted diseases infection are more relevant considerations. Further development with the ring could think about making the ring carry more than one drugs, so a comprehensive effect of contraceptives and disease prevention can be achieved simultaneously.
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